CXCL16 is a novel, unique CXC chemokine with characteristics of CC chemokines and structurally related to CX3CL1 since both are membrane bound chemokines. CXCL16 is expressed in antigen presenting cells including CD19 + B cells and CD14 + monocyte/macrophages. We have found that this chemokines is also expressed in glomerular endothelial cells. This chemokine was markedly induced in the glomeruli of Wistar-Kyoto rats with anti-glomerular basement membrane (GBM) antibody (Ab) glomerulonephritis (GN) throughout the disease and CXCL16 induced migratory response of glomerular infiltrate isolated from this model of GN. This data suggest that CXCL16 may play a critical role in the leukocyte influx in immune-mediated inflammation in the kidney. We propose to study the mechanism of CXCL16 regulation and signaling in glomerular endothelial cells as well as the CXCL16/CXCR6 interactions mainly between glomerlular endothelial cells and monocyte/macrophages. We will study the potential role of CXCL16 in leukocyte capture and firm adhesion and whether this effects can be mediated under physiological flow conditions. We will further dissect this multidomain chemokine to determine the functional domain(s) in CXCL16-mediated adhesion. In in vivo studies we will analyze the functional role of CXCL16 during the progression of acute injury to renal fibrosis in a model of GN and tubulointerstitial nephritis by generating blocking antibodies. Further we will investigate whether blocking CXCL16 could intervene in the progressive phase of established GN and tubulointerstitial nephritis. These findings are expected to offer an approach to therapy that influences the regulation of chemokine/chemokine receptor to modulate renal diseases that may be CXCL16 associated, including tubulointerstitial nephritis, GN and endothelium-related inflammatory diseases such as vasculitis, allograft rejection, ischemia/reperfusion injury and atherosclerosis.